Non-insulin-dependent diabetes mellitus (NIDDM) is a disorder of glucose homeostasis characterized by impaired insulin action (insulin resistance) and impaired insulin production. It is widely held that genetic factors play a key role in the development of insulin resistance and NIDDM. Insulin resistance is inherited in as a non-Mendelian trait, the pathogenesis of which likely involves genetic heterogeneity and polygenic inheritance. We are interested in dissecting the genetic components of insulin resistance using mouse and human genetic models. This project focuses on the characterization of mice with targeted mutations in the pathway of insulin action. To generate a mouse model of insulin resistance, we have initially introduced a mutant allele of the insulin receptor in mice. Homozygosity for a null insulin receptor allele causes neonatal death from ketoacidosis, whereas heterozygosity for this mutation is associated with hyperinsulinemia, a sign of insulin resistance. These mice provide a valuable model to further characterize the mechanism of insulin action and its impairment in NIDDM. Three broad areas of investigation are being pursued: a. the generation of transgenic knock-outs in which expression of insulin receptors has been restored either in a tissue-specific fashion or with mutant insulin receptors; b. the derivation of cell lines from the knock-out mice to analyze the insulin signaling pathway, and c. the identifying of additional "diabetogenic" genes that interact with the insulin receptor gene in a polygenic model of insulin resistant-diabetes. Genetic abnormalities identified through these studies will be complemented by studies of NIDDM patients.